Synaptic inhibition and its role in the Central Nervous System (CNS)

Chapter 1: General Introduction

1.1. Synaptic inhibition and its role in the Central Nervous System (CNS)

Central nervous system (CNS) consists of brain and spinal cord. It plays a fundamental role in manipulating the sensation, memory, movement, recognition, emotion, etc. in mammalians. Neurons act as the basic functioning unit of the central nervous system. Electrical and chemical signals transmitting through the network of neurons coordinate the communication in the CNS. Excitatory and inhibitory neurotransmission can be classified according to their various physiological effects on the body. Excitatory synapses mainly express the AMPARs (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors), NMDARs (N-methyl-D-aspartic acid receptor), nAChRs (Nicotinic acetylcholine receptors), etc.

The activation of these ligand-gated ion channels causes depolarization by influx of cations (MOLNAR et al. 2002; BAKIRI et al. 2008), which triggers the action potential and the neuron firing (MCQUISTON u. MADISON 1999; BREDT u.

NICOLL 2003; ARNAIZ-COT et al. 2008; HAMILTON et al. 2008). On the other hand, inhibitory neurotransmission suppresses the excitability of the neural circuits.

GABA (-aminobutyric acid) and glycine function as the major inhibitory neurotransmitters in the CNS. The ionotropic GABAA receptors exist throughout the central nervous system (LUDDENS u. KORPI 1995; MOHLER 2007, 2009), with specific subtype distribution in certain regions. Receptors containing , ,  or

subunits combing with  and subunits are most prevalent in the CNS (MOHLER 2007).-containing GABAA receptors are most widely distributed throughout the brain (MOHLER 2007) and abundantly expressed in the occipital cortex and cerebellum (HEISS u. HERHOLZ 2006).  and GABAA receptors are the main subtypes expressed in basal forebrain and spinal cord (MOHLER 2007, 2009). In limbic areas (hippocampus, anterior cingulated cortex, insular cortex, etc),

-containing receptors are the major subtype (HEISS u. HERHOLZ 2006; SPERK

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et al. 2009). Distinct pharmacological characteristics and localization patterns of multiple GABAA receptors are essential for their mediating inhibitory neurotransmission under various physiological conditions.

Ligand-gated glycine ion channels manipulate voluntary motor control, reflex response, and the processing of sensory signals in the CNS (RAJENDRA et al. 1997).

Like GABAA receptors, glycine receptors are also distributed throughout the CNS (RAJENDRA et al. 1997; BETZ et al. 1999; J. H. YE 2008), but prominent in the brainstem and spinal cord (RAJENDRA et al. 1997; LAUBE et al. 2002; BAER et al.

2009). Until now, four and one  subunits have been identified (CHALPHIN u.

SAHA 2010). /Heteromeric glycine receptors are widely expressed in the adult mammalian CNS, whereas fetal glycine receptors are thought to be homomers composed of five subunits (MALOSIO et al. 1991; RAJENDRA et al. 1997; BETZ et al. 1999; CHALPHIN u. SAHA 2010).

Ion channels mediating the hyperpolarization of cells work for the inhibitory neurotransmission. On the other hand, excitatory transmission is induced by the activation of glutamatergic receptors (AMPARs, NMDARs), serotonin (5-hydroxytryptamine, 5-HT₆) receptors (RAMAGE 2006), voltage-gated sodium channels (RAMAGE 2006; FEIGENSPAN et al. 2010), tonic activation of muscarinic acetylcholine receptors (mAChRs) (DASARI u. GULLEDGE 2011; GUNDISCH u.

EIBL 2011), etc. For the role in balancing the neuronal excitability, bio-physiological processes suppressing the excitatory transmission indirectly contribute to the inhibition of the neural network. Various transporters (DUNLOP 2006; RUDNICK 2006; SHELDON u. ROBINSON 2007; PRATUANGDEJKUL et al. 2008; A. LEE u.

POW 2010; DE GROOT u. SONTHEIMER 2011) removing the excitatory neurotransmitters from the synapse help terminating the excitatory neurotransmission.

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Excitatory amino acid transporters (EAATs) clear extracellular glutamate, the most principal excitatory neurotransmitter (VOLPI et al. 2012) in the CNS. So far, 5 subtypes of EAATs have been identified in humans (as well as in rodents), with distinct electrophysiological properties and distribution patterns in the brain. EAAT1 (GLAST) and EAAT2 (GLT-1) are mainly expressed in glia cells (MIRALLES et al.

2001; SUCHAK et al. 2003) while EAAT3 (EAAC1) and EAAT4 are located in neurons (HU et al. 2003; MARAGAKIS et al. 2004). EAAT5 is the retina-specific isoform (ARRIZA et al. 1997). EAAT1, EAAT2 and EAAT3 elicit currents with a small component of anion conductance while EAAT4 and EAAT5 mediate predominant anion currents (WADICHE et al. 1995; WATZKE u. GREWER 2001;

MELZER et al. 2003; BEART u. O'SHEA 2007; GAMEIRO et al. 2011).

The integration of the electrophysiological signals in the CNS helps coordinating the activities of the body. Disturbances of the synaptic inhibition lead to neurological disorders in movement, recognition, sedation, emotion, etc. Malfunction in GABAergic inhibition is directly associated with epileptic seizures. A point mutation A322D in 1 subunit of GABAA receptors, found in the multigeneration juvenile myoclonic epilepsy (JME) family, results in a reduced GABA affinity and a decreased receptor expression in the cell membrane (KRAMPFL et al. 2005; BRADLEY et al.

2008). A G32R mutation occurring in the 3 subunit of GABAA receptors is associated with childhood absence epilepsy (CAE), with a smaller macroscopic current compared to the wild-type receptor, as well as a changed subtype compostion in the membrane (GURBA et al. 2012). The prominent changes in specific subtypes of GABAA receptors were observed in tissues from the rat model of temporal lobe epilepsy (FRITSCHY et al. 1999; LEROY et al. 2004). Other diseases like schizophrenia, depression, Alzheimer's disease can be also triggered by an impaired GABAergic transmission (GONZALEZ-BURGOS et al. 2011; BRICKLEY u.

MODY 2012; KOH et al. 2012; LIMON et al. 2012). Defects of glycineric neurotransmission give rise to hyperekplexia (ZHOU et al. 2002; HANSON u.

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CZAJKOWSKI 2008; DAVIES et al. 2010; BHIDAYASIRI u. TRUONG 2011), characterized by pronounced startle responses to tactile or acoustic stimuli and hypertonia. Many mutations in glycine receptors (PLESTED et al. 2007;

AL-FUTAISI et al. 2012; AL-OWAIN et al. 2012; LAPE et al. 2012) and in glycine transporters (CARTA et al. 2012; GIMENEZ et al. 2012) associated with this disease have been characterized. Glycine receptors also act as the most important ion channels in alleviating the neuropathic pain (DOHI et al. 2009). Potentiating

3-subunit-containing GlyRs is considered as a promising pharmacological strategy in analgesia (LYNCH u. CALLISTER 2006; XIONG et al. 2012). It is not surprising that functions of the glutamate transporters are highly correlated with some neurological disorders, since they play an important role in preventing the cell excitotoxicity in the CNS. The impaired glutamate recycling by reduced EAATs expression in brains of Alzheimer's disease (AD) patients may contribute to the pathophysiology of AD (JACOB et al. 2007; K. H. CHEN et al. 2011). Recent studies on rat models demonstrate the involvement of GLT-1 in the pathogenesis of ischemic damage in brain (ZHANG et al. 2010; HARVEY et al. 2011;

KETHEESWARANATHAN et al. 2011). In amyotrophic lateral sclerosis (ALS), the neuronal injury is induced by the extracellular glutamate toxicity (KANAI u.

HEDIGER 2003). Decreased membrane expression of GLT-1 (VANONI et al. 2004) and its impaired activity (GOURSAUD et al. 2009) were found in rat models of ALS.

In a G93A SOD1 mice model, treatment with -Lactam antibiotics activated the gene and functional activity of GLT-1, thus delayed the neuron loss and increased the mice survival (ROTHSTEIN et al. 2005).